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- Mishra, A., et al.
(author)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Journal article (peer-reviewed)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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| 2. |
- Amouzou, A, et al.
(author)
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Health service utilisation during the COVID-19 pandemic in sub-Saharan Africa in 2020: a multicountry empirical assessment with a focus on maternal, newborn and child health services
- 2022
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In: BMJ global health. - : BMJ. - 2059-7908. ; 7:5
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Journal article (peer-reviewed)abstract
- There are concerns about the impact of the COVID-19 pandemic on the continuation of essential health services in sub-Saharan Africa. Through the Countdown to 2030 for Women’s, Children’s and Adolescents’ Health country collaborations, analysts from country and global public health institutions and ministries of health assessed the trends in selected services for maternal, newborn and child health, general service utilisation.MethodsMonthly routine health facility data by district for the period 2017–2020 were compiled by 12 country teams and adjusted after extensive quality assessments. Mixed effects linear regressions were used to estimate the size of any change in service utilisation for each month from March to December 2020 and for the whole COVID-19 period in 2020.ResultsThe completeness of reporting of health facilities was high in 2020 (median of 12 countries, 96% national and 91% of districts ≥90%), higher than in the preceding years and extreme outliers were few. The country median reduction in utilisation of nine health services for the whole period March–December 2020 was 3.9% (range: −8.2 to 2.4). The greatest reductions were observed for inpatient admissions (median=−17.0%) and outpatient admissions (median=−7.1%), while antenatal, delivery care and immunisation services generally had smaller reductions (median from −2% to −6%). Eastern African countries had greater reductions than those in West Africa, and rural districts were slightly more affected than urban districts. The greatest drop in services was observed for March–June 2020 for general services, when the response was strongest as measured by a stringency index.ConclusionThe district health facility reports provide a solid basis for trend assessment after extensive data quality assessment and adjustment. Even the modest negative impact on service utilisation observed in most countries will require major efforts, supported by the international partners, to maintain progress towards the SDG health targets by 2030.
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| 3. |
- Islar, Mine, et al.
(author)
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Diverse values of nature for sustainability
- 2022
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In: Nature. - 0028-0836 .- 1476-4687. ; 620, s. 813-823
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Journal article (peer-reviewed)abstract
- Twenty-five years since foundational publications on valuing ecosystem services for human well-being1,2, addressing the global biodiversity crisis3 still implies confronting barriers to incorporating nature’s diverse values into decision-making. These barriers include powerful interests supported by current norms and legal rules such as property rights, which determine whose values and which values of nature are acted on. A better understanding of how and why nature is (under)valued is more urgent than ever4. Notwithstanding agreements to incorporate nature’s values into actions, including the Kunming-Montreal Global Biodiversity Framework (GBF)5 and the UN Sustainable Development Goals6, predominant environmental and development policies still prioritize a subset of values, particularly those linked to markets, and ignore other ways people relate to and benefit from nature7. Arguably, a ‘values crisis’ underpins the intertwined crises of biodiversity loss and climate change8, pandemic emergence9 and socio-environmental injustices10. On the basis of more than 50,000 scientific publications, policy documents and Indigenous and local knowledge sources, the Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES) assessed knowledge on nature’s diverse values and valuation methods to gain insights into their role in policymaking and fuller integration into decisions7,11. Applying this evidence, combinations of values-centred approaches are proposed to improve valuation and address barriers to uptake, ultimately leveraging transformative changes towards more just (that is, fair treatment of people and nature, including inter- and intragenerational equity) and sustainable futures.
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| 6. |
- Norström, Albert V., 1979-, et al.
(author)
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The programme on ecosystem change and society (PECS) - a decade of deepening social-ecological research through a place-based focus
- 2022
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In: Ecosystems and People. - : Informa UK Limited. - 2639-5908 .- 2639-5916. ; 18:1, s. 598-608
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Journal article (peer-reviewed)abstract
- The Programme on Ecosystem Change and Society (PECS) was established in 2011, and is now one of the major international social-ecological systems (SES) research networks. During this time, SES research has undergone a phase of rapid growth and has grown into an influential branch of sustainability science. In this Perspective, we argue that SES research has also deepened over the past decade, and helped to shed light on key dimensions of SES dynamics (e.g. system feedbacks, aspects of system design, goals and paradigms) that can lead to tangible action for solving the major sustainability challenges of our time. We suggest four ways in which the growth of place-based SES research, fostered by networks such as PECS, has contributed to these developments, namely by: 1) shedding light on transformational change, 2) revealing the social dynamics shaping SES, 3) bringing together diverse types of knowledge, and 4) encouraging reflexive researchers.
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| 7. |
- Codilean, A. T., et al.
(author)
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OCTOPUS database (v.2)
- 2022
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In: Earth System Science Data. - : Copernicus GmbH. - 1866-3508 .- 1866-3516. ; 14:8, s. 3695-3713
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Journal article (peer-reviewed)abstract
- OCTOPUS v.2 is an Open Geospatial Consortium (OGC) compliant web-enabled database that allows users to visualise, query, and download cosmogenic radionuclide, luminescence, and radiocarbon ages and denudation rates associated with erosional landscapes, Quaternary depositional landforms, and archaeological records, along with ancillary geospatial (vector and raster) data layers. The database follows the FAIR (Findability, Accessibility, Interoperability, and Reuse) data principles and is based on open-source software deployed on the Google Cloud Platform. Data stored in the database can be accessed via a custom-built web interface and via desktop geographic information system (GIS) applications that support OGC data access protocols. OCTOPUS v.2 hosts five major data collections. CRN Denudation and ExpAge consist of published cosmogenic Be-10 and Al-26 measurements in modern fluvial sediment and glacial samples respectively. Both collections have a global extent; however, in addition to geospatial vector layers, CRN Denudation also incorporates raster layers, including a digital elevation model, gradient raster, flow direction and flow accumulation rasters, atmospheric pressure raster, and CRN production scaling and topographic shielding factor rasters. SahulSed consists of published optically stimulated luminescence (OSL) and thermoluminescence (TL) ages for fluvial, aeolian, and lacustrine sedimentary records across the Australian mainland and Tasmania. SahulArch consists of published OSL, TL, and radiocarbon ages for archaeological records, and FosSahul consists of published late-Quaternary records of direct and indirect non-human vertebrate (mega)fauna fossil ages that have been systematically quality rated. Supporting data are comprehensive and include bibliographic, contextual, and sample-preparation- and measurement-related information. In the case of cosmogenic radionuclide data, OCTOPUS also includes all necessary information and input files for the recalculation of denudation rates using the open-source program CAIRN. OCTOPUS v.2 and its associated data curation framework allow for valuable legacy data to be harnessed that would otherwise be lost to the research community. The database can be accessed at https://octopusdata.org (last access: 1 July 2022). The individual data collections can also be accessed via their respective digital object identifiers (DOIs) (see Table 1).
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| 8. |
- Gubinelli, F., et al.
(author)
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Lateralized deficits after unilateral AAV-vector based overexpression of alpha-synuclein in the midbrain of rats on drug-free behavioral tests
- 2022
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In: Behavioural Brain Research. - : Elsevier BV. - 0166-4328. ; 429
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Journal article (peer-reviewed)abstract
- Background: Preclinical rodent models of Parkinson's aim to recapitulate some of the hallmarks of the disease as it presents in humans, including the progressive neuronal loss of dopaminergic neurons in the midbrain as well as the development of a behavioral phenotype. AAV vector-based models of alpha-synuclein overexpression are a promising tool to achieve such animal models with high face and predictive validity. Objective: We have developed a preclinical rodent model of Parkinson's disease using an AAV-vector based overexpression of human alpha-synuclein. In the present work we characterize this model on a behavioral and histopathological level. Methods: We use a AAV9 vector for transgene delivery to overexpress human alpha-synuclein under a CBA promoter. We compare the behavioral and histopathological changes to a AAV vector control group where the transgene was omitted and to that of a 6-OHDA lesion control. We assessed the behavioral performance of these three groups on a series of tests (Cylinder, Stepping, Corridor) at baseline and up to 22 weeks post-injection at which point we performed electrochemical recordings of dopamine kinetics. Results: The overexpression of human alpha-synuclein led to the progressive manifestation of behavioral deficits on all three behavioral tests. This was accompanied with impaired dopamine release and reuptake kinetics as demonstrated by electrochemical detection methods. Histopathological quantifications corroborated the findings that we induced a moderate cell loss with remaining cells displaying pathological markers which are abundant in the brains of human PD patients. Conclusions: In the present work we developed a characterized a rat model of PD that closely mimics human disease development and pathology. Such model will be of great use for investigation of disease mechanisms and early therapeutic interventions.
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